Goal 2: Reduce Human Disease

Evidence based approaches to Red Blood Cell transfusion

What are the optimal RBC transfusion thresholds for adult and pediatric cancer patients undergoing chemotherapy regimens that may improve functional status and quality of life?

Submitted by (@nareg.roubinian)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Cancer patients undergo intensive medical and surgical therapies to treat their underlying disease. Treatment commonly results in anemia requiring RBC and platelet transfusions to support the patient through the hypoproliferative phase of chemotherapy. This is particularly true for those patients requiring hematopoetic stem cell transplantation (HSCT). Following therapy, cancer outpatients commonly receive RBC transfusions for weeks to months to maintain their functional status.

 

Common causes of death in patients with hematological malignancies and other cancers are infections and bleeding. A meta-analysis of clinical trials suggested that liberal transfusion is associated with greater risk of infection. Conversely, restrictive transfusion could adversely affect quality of life and functional status in oncology populations. In addition, pre-clinical and clinical studies support that concomitant anemia and thrombocytopenia significantly compound bleeding risk, and that hemostasis can be optimized in thrombocytopenia by maintaining a higher hematocrit. Although bleeding risks in relation to platelet transfusion thresholds are well studied in patients with hematological malignancy, optimal hemoglobin levels in thrombocytopenic patients are not known. Despite the significant allocation of blood components to cancer patients as a whole, RBC transfusion practices are not well studied within this group.

Feasibility and challenges of addressing this CQ or CC :

Randomized controlled clinical trials and other studies investigating optimal transfusion thresholds and other measures of practice are required to provide health care providers with evidence to guide one of the most common therapies administered in the setting of malignancy. The clinically important end points of well-designed studies could include: 1) quality of life and functional status for both inpatients and outpatients; 2) neurocognitive development in pediatric populations; 3) bleeding events / bleeding scores; 4) impact on immunity including immunomodulation and infection; 5) reconstitution of hematopoiesis; and 6) survival and/or recurrence of disease.. Besides a generalizable study population, certain target populations of interest are those with high risk disease, HSCT patients, patients undergoing radiation therapy, and pediatric patients.

 

There are >1.6 million new cases of cancer annually in the USA, including >50,000 with leukemia and >6,000 with HSCT. Cancer therapies are rapidly advancing in the era of genomics and immunotherapy. Capitalizing on the tradition of research in cancer, single and multicenter studies of RBC transfusion are feasible using randomized controlled designs in conjunction with clinical trials of chemotherapeutic regimens. The results of these studies will impact a large patient population’s quality of life, and may ultimately impact healthcare cost and blood demand.

Name of idea submitter and other team members who worked on this idea : Nareg Roubinian, MD and Naomi Luban, MD for the 2015 NHLBI State of the Science in Transfusion Medicine

Voting

43 net votes
61 up votes
18 down votes
Active

Goal 1: Promote Human Health

Nefarious substances in the US blood supply

Prescription and illicit drug is everpresent in the US, which can potentially result in controlled substances entering the US blood supply. Passive transfer of immune allergens is only anecdotally been reported as peanut allergens, fish allergens, and contrast material. However, US blood donors are only screened for a limited number of medications on the universal donor health questionnaire at time of collection. What, ...more »

Submitted by (@garrett.s.booth)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Of the nearly 15 million blood products collected in the US (National Blood Collection and Utilization Survey), what percent of donations capture additional substances like medications and illicit substances. Healthcare providers may be unaware of potential adverse transfusion reactions that could arise from potent allergens within the products themselves.

If additional donor screening is required to reduce the number of medications/drugs entering the US blood supply, how best to do this? Via blood toxicology, urine toxicology, hair toxicology? Is there a need to marry the donor drug history with the recipient allergy list?

Feasibility and challenges of addressing this CQ or CC :

These questions would require blood collection centers to potentially revise how they screen blood donors. How and when to probe donations or donors will require extensive medical-legal investigation.

Name of idea submitter and other team members who worked on this idea : LostInNashville

Voting

-11 net votes
6 up votes
17 down votes
Active

Goal 2: Reduce Human Disease

Blood Donor and Component Factors that Influence Clinical Outcomes of Transfusion

Are donor factors (age/sex), whole blood processing methods and/or red cell storage solutions associated with in-hospital mortality and/or other measures of transfusion efficacy or harm in patients who have received red cell transfusions?

Submitted by (@anne.eder)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

There is growing evidence that donor factors (age, race-ethnicity, and/or sex), method of whole blood processing, and/or the additive solution used for red cell storage could affect the quality of the red cell product and contribute to patient adverse events. For example, red cell rigidity and oxygen saturation varies between premenopausal women and postmenopausal women and men, suggesting that donor age and/or sex may be important factors affecting red cell quality and patient outcomes. A retrospective Canadian study suggested that older blood was associated with in-hospital mortality until 2006; however, after that time the risk of in-hospital mortality increased when fresher blood was transfused. This change coincided with introduction of the buffy coat method suggesting that whole blood processing methods may affect patient outcomes.

Feasibility and challenges of addressing this CQ or CC :

The most efficient way to explore these issues is through the use of large dataset that can link donor demographics, product processing and recipient transfusion and outcome data. Recipient datasets are available and the feasibility of linking blood donor and blood product information has been demonstrated, making it possible to address the research question stated above.

Name of idea submitter and other team members who worked on this idea : Dana Devine PhD and Anne Eder MD PhD for the 2015 NHLBI State of the Science in Transfusion Medicine

Voting

24 net votes
34 up votes
10 down votes
Active

Goal 3: Advance Translational Research

Comprehensive Assessment of Cardiovascular Physiology: Imaging of Structure, Function and Blood Flow

The development of cardiovascular disease is associated with changes in structure, function and blood flow within a complex and highly interconnected system. Current diagnostic tools focus on individual elements of the cardiovascular system and/or relatively simple parameters which do not reflect the true underlying pathophysiology. A novel multi-modular and multi-parametric approach based on new and promising imaging ...more »

Submitted by (@mmarkl)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Voting

1 net vote
1 up votes
0 down votes
Active

Goal 1: Promote Human Health

Role of the lymphatic system in heart, lung, blood, sleep health and diseases

What is the role of lymphatic system in normal function of the heart? Do dysfunctional lymphatics contribute to heart failure? Do lymphatics have a role in recovery after MI? It has been reported that lymphatic vasculature transport HDL during reverse cholesterol transfer. Do lymphatics have a role in atherosclerosis? What is the contribution of lymphatic system to asthma or COPD? Does the lymphatic system contribute ...more »

Submitted by (@nhlbiforumadministrator1)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Understanding how lymphatic system contributes to normal physiology of heart, lung, blood, sleep systems will help also lead to new approaches for treatment of heart, lung, blood, sleep diseases.

Feasibility and challenges of addressing this CQ or CC :

Basic understanding of the development and hemodynamics of the lymphatic system and reagents to study the lymphatic function are available.

Lymphatic vasculature is essential for fluid hemostasis in the body, collects and returns the protein- and lipid-rich interstitial fluid to blood circulation, and also involved in immune cell trafficking and inflammation. Given these important physiological roles, function of the lymphatic system is expected to contribute to normal physiology of organs and its dysfunction to major diseases. There is very little or no information how the lymphatic system contribute to health and diseases of the cardiovascular, pulmonary and blood systems, and there are many unanswered questions. Answers to these questions may lead to new approaches for treatment of major HLB diseases. Main challenge is to get heart, lung, blood, sleep investigators interested in studying the contribution of the lymphatic system to heart, lung, blood, sleep health and diseases.

Name of idea submitter and other team members who worked on this idea : NHLBI Staff

Voting

50 net votes
77 up votes
27 down votes
Active

Goal 3: Advance Translational Research

Lipid and lipoprotein metabolism in the CNS

The analysis of lipoprotein metabolism has traditionally been restricted to the easily accessible circulation and peripheral tissues. Very little work has been done behind the blood brain barrier, where many of the lipid carrying or metabolizing genes are also expressed. Yet we know very little about their functions there, although for instance ApoE4 is THE primary risk factor for late-onset Alzheimer's disease. Conventional ...more »

Submitted by (@joachim.herz)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Alzheimer's disease currently affects ~6 million Americans and costs upwards of 200 billion $ per year. Lipoprotein components, specifically containing ApoE and ApoJ, are the predominant risk factors for late-onset AD. The neuroscience community lacks the expertise in lipoprotein biology that is necessary to solve this enormous socioeconomic problem.

The NHLBI is ideally positioned to assume a leadership role to address this major challenge, which transcends traditional institute boundaries.

Feasibility and challenges of addressing this CQ or CC :

This is perfectly feasible, I am addressing this problem for years, there are clear rational approaches for it, but far too few investigators have picked up the challenge.

 

I would be most interested in discussing strategies and solutions to this pressing challenge in detail with the NHLBI!

Name of idea submitter and other team members who worked on this idea : Joachim Herz

Voting

-4 net votes
7 up votes
11 down votes
Active

Goal 2: Reduce Human Disease

Inflammation: what is the role of the blood microbiome?

Blood is not continuously sterile. Data from dental studies, blood donors, and random blood cultures document that "normal" human blood often harbors microbes. Sepsis only occurs when immunological regulatory systems fail. Growing evidence link subclinical, potentially transient bacteremia to cardiovascular and other diseases. Could many of the diseases associated with inflammatory markers represent either continuous ...more »

Submitted by (@kevinfiscella)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

A central scientific question is whether the blood microbiome has immunologic significance or not. Does it represent a largely incidental, trivial finding or does it represent an important source for immunologic activity?

 

This change in scientific paradigm could have major implications for research including providing a unifying explanation for unexplained phenomena including potential mechanisms related to disparate conditions including CVD, HTN, preterm births, CNS disorders, auto-immune diseases, etc. For example, the inflammation associated with obesity may result from differences in not only the micriobiome of the GI tract but also blood. Transient bacteremia might also explain effects of psychologic stress, smoking, and diet via permeability effects via other microbiomes.

 

Historically, transient, subclinical bacteremia has been regarded as an incidental finding of little consequence outside of selected conditions e.g. bacterial endocarditis and severe immune suppression. The concept that subclinical, transient bacteremia (and potentially very low level viremia) have both beneficial (adaptive immunity) and harmful (inflammatory) significance creates new directions for research and ultimately new targets for intervention including regulators of permeability on various barriers between different microbiomes. e.g blood and GI tract, or blood and oral cavity etc.

Feasibility and challenges of addressing this CQ or CC :

One challenge is methodologic. Standard blood cultures miss low level and/or transient bacteremia. New approaches, e.g. 16 rDNA PCR etc offer promise but advances in methods are needed to capture potentially intermittent phenomena.

 

Another challenge is that the blood microbiome is likely polymicrobial and potentially dynamic with bursts of different microbes resulting from different sources e.g. oral cavity,skin, GI tract, UG tract, lung etc. Like other microbiomes, it is probably more of an ecological system embedded within other micorbiome systems. Methods need to account for for the potential large diversity in blood microbes with likely differing significance including potential competition and synergy between different microbes whether intra or extracellular.

 

A third challenge relates to the potential longitudinal and developmental implications. Potentially blood microbiome effects are relatively small, but cumulative and developmentally sensitive.This will require longitudinal studies in humans (and animal models) including studies done during pregnancy and other critical developmental periods.

 

A final challenge is modeling. This includes disentangling effects from established human microbiomes from the blood and establishing directions of effects between blood microbiomes and immune activity. Methods applicable to complex adaptive systems with non-linear, time dependent effects are likely required.

Name of idea submitter and other team members who worked on this idea : Kevin Fiscella, MD, MPH

Voting

15 net votes
25 up votes
10 down votes
Active

Goal 2: Reduce Human Disease

Would patients with pulmonary arterial hypertension (PAH) benefit from background anticoagulation in addition to their PAH-targe

Pulmonary hypertension (PH) is a complex, progressive condition characterized by high blood pressure in the lungs. For several decades, oral anticoagulation has been recommended by some societies for patients with a specific form of PH called pulmonary arterial hypertension. However, the evidence currently supporting this recommendation is very limited. To date, no prospective randomized clinical trial has been completed ...more »

Submitted by (@katherinek)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

The evolution of the anticoagulation recommendation in pulmonary arterial hypertension (PAH) is a relatively logical one at face value. Early in the modern era of PAH management, a “thrombosis” in the small pulmonary arteries was identified and described; studies since then have demonstrated hypercoagulability in patients with severe disease. Together, these observations led to a theory that in-situ thrombosis contributed to the PAH disease progression and a belief that anticoagulation should be beneficial. The empirical evidence currently supporting this recommendation comes mostly from a retrospective cohort study of the European COMPERA PH registry and a systematic review of 7 retrospective cohort studies that are at least 10 years old—2 of which did not suggest a survival benefit—and in a time where only 4 of the widely used PAH-targeted therapies were approved by the FDA. Purely based on observational evidence with a number of potential biases, warfarin (Coumadin) is widely used in PAH management to this day. Warfarin in this patient population is not without its risks, as some subgroups of PAH patients are at increased risk of bleeding complications based on their disease process alone. Assessing the true benefit of this widely used background therapy could allow clinicians and patients to more accurately weigh the risks and burden of anticoagulation with a true understanding of the survival benefit.

Feasibility and challenges of addressing this CQ or CC :

Addressing this compelling question is indeed feasible through an NIH-sponsored randomized, double-blind, placebo-controlled trial of anticoagulation in patients with certain types of pulmonary arterial hypertension.

Name of idea submitter and other team members who worked on this idea : Katherine Kroner, Michael Patrick Gray, PHA

Voting

62 net votes
68 up votes
6 down votes
Active

Goal 2: Reduce Human Disease

How can we increase the pharmaceutical clinical research of targeted therapies in pediatric PAH patients, including encouraging

Clinical research, especially randomized pharmaceutical clinical trials, poses many unique challenges compared to research in adult subjects. In pulmonary arterial hypertension, a disease characterized by high blood pressure of the lungs with increased pulmonary vascular resistance leading to right ventricular failure, there are 12 FDA-approved PAH-targeted therapies for adults. None of these medications are currently ...more »

Submitted by (@katherinek)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Pulmonary arterial hypertension is a heterogeneous condition generally characterized by high blood pressure in the lungs and increased pulmonary vascular resistance that leads to right heart failure if left untreated. Though some causes of PAH are seen in both adult and pediatric populations, some etiologies are seen exclusively in pediatric populations, including persistent pulmonary hypertension of the newborn, bronchopulmonary dysplasia, lung hypoplasia, and alveolar capillary dysplasia. Despite these differences in disease etiology, and known physiologic differences in pediatric populations, inhaled nitric oxide (iNO) in the acute setting is the only approved medication for PAH treatment in children. A number of issues have decreased pediatric PAH pharmaceutical research, including protection of the pediatric population as vulnerable subjects, principle of scientific necessity, balance of risk and potential benefit, parental consent/child assent, and feasibility of pediatric clinical trial design and implementation. Encouraging clinical trials of existing adult medications and potentially emerging, novel agents specifically for pediatrics—either through direct sponsorship or regulatory incentives—would not only lead to better outcomes for pediatric PAH patients, but potentially to a better and more comprehensive characterization of the developing pulmonary vascular system and right ventricle.

Feasibility and challenges of addressing this CQ or CC :

Several challenges exist for addressing this critical challenge. First, there are a number of differences between conducting clinical research in pediatric populations compared to adult populations. This not only includes the broad items referenced above, but items as noted by Rose and colleagues related to clinical trial design and analysis including (1) accepted age-matched normal ranges for laboratory values; (2) requirements for the validation of clinical endpoints for the assessment of efficacy and safety; and (3) standards for long-term safety monitoring and pharmacovigilance (Rose K, et al. NEJM 2005). Sponsorship of this type of clinical research is a second concern, which could either be mitigated by direct support from the National Institutes of Health of pediatric PAH clinical trials or in regulatory changes incentivizing pediatric clinical research in rare diseases.

Name of idea submitter and other team members who worked on this idea : Katherine Kroner, Michael Patrick Gray, PHA

Voting

66 net votes
76 up votes
10 down votes
Active

Goal 1: Promote Human Health

The Human Virome and Host Interactions in Heart, Lung, and Blood

What are the unknown elements of the human virome, and what host-virome interactions affect the heart, lung, and blood health and diseases? A major challenge has been the need for in vitro culture systems and animal models for studying the virome, which is a significant limitation that has forced current studies of the virome to be mostly descriptive. NHLBI has supported one research group to identify human virome and ...more »

Submitted by (@nhlbiforumadministrator)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

• The virome contains the most abundant and fastest mutating genetic elements on Earth. The human virome is constituted of viruses that infect host cells, virus-derived elements in our chromosomes, and viruses that infect the broad array of other types of organisms that inhabit us. The virome may influence the host in profound ways independent of classical viral disease. The immune system is continuously stimulated by chronic systemic viruses and this aspect of host-microbiome interactions appears specific to the virome. The virome is considered one of the drivers of idiopathic systemic inflammation that has been linked to many of the most severe public health threats, including cardiovascular diseases. Disruptions in immunity by immunosuppressing events can undoubtedly alter the interactions of the virome with the host. However, little research has been done in all of these aspects other than limited descriptive studies to identify the presence or composition of the human virome. The NHLBI Microbiome Working Group in June 2014 clearly identified under-representation of studies of the human virome. Identification and characterization of unknown viral elements of the human virome and research on the interactions with the host will allow exploration of their impact on heart, lung and blood health and diseases, including impact in the presence of immunosuppression with the host such as in AIDS or HIV infection.

Feasibility and challenges of addressing this CQ or CC :

This initiative is feasible because of new technologies that have been developed recently such as the deep sequencing techniques. The initiative is also timely in that research supported by the NIH Human Microbiome Program and other programs has allowed us to better understand microbiome, especially bacteria in and on humans, and we began to realize the magnitude of the virome. This initiative will attract more investigators to not only identify more elements of the virome but more importantly to understand the roles of the human virome in heart, lung and blood health and diseases, and eventually to help develop diagnostic and intervention strategies.

Name of idea submitter and other team members who worked on this idea : NHLBI Staff

Voting

13 net votes
29 up votes
16 down votes
Active

Goal 3: Advance Translational Research

Genome Editing and Gene Therapy

There is a critical need for the establishment of strategies that will determine the efficacy, safety, and toxicity of genome editing techniques specifically in hematologic diseases.

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Inherited monogenic hematologic diseases such as hemophilia, beta-thalassemia and sickle cell disease are prime targets for future application of genome editing technology. However, studies are still needed to advance our understanding of the biology of genome editing as well as determine which other disorders are amenable to genome editing correction. Emphasis on preclinical research that focuses on determining the accuracy, safety and efficiency of this technology in order to help minimize off-target mutations and reduce toxicity, is essential for effective translation of this technology into the clinic. Once preclinical efficacy is established, support will be needed for clinical vector production, toxicity testing of the vectors/reagents used, and the performance of clinical trials. The gene correction strategies developed for inherited disorders will also be attractive for other hematologic diseases, and autoimmune disorders like lupus, rheumatoid arthritis, and type I diabetes). There is also a critical need for supporting preclinical validation studies, scale-up and GMP cell manufacturing, all of which could be shared infrastructures across multiple diseases in the NHLBI portfolio.

Name of idea submitter and other team members who worked on this idea : Alice Kuaban on behalf of the American Society of Hematology (ASH)

Voting

69 net votes
87 up votes
18 down votes
Active

Goal 1: Promote Human Health

Causes of blood clotting in lungs

What causes blood clotting in the lungs, and what are its side effects?

Submitted by (@nhlbiforumadministrator1)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Name of idea submitter and other team members who worked on this idea : Joseph Erikitai

Voting

-3 net votes
10 up votes
13 down votes
Active